The long term objective of this project is to determine the role of cortisol and its metabolites in the pathogenesis of primary open angle glaucoma (POAG) and to develop therapeutic modalities which are of value in the treatment of this disorder. Most patients with POAG show a marked sensitivity to the intraocular pressure raising effects of topical and systemic glucocorticoids. It has been our working hypothesis that this is related to an abnormality in cortisol metabolism in ocular tissue. Indeed, an alteration in cortisol metabolism has recently been demonstrated in cells cultured from human trabeculectomy specimens from POAG patients (TMPOAG cells). This alteration in metabolism led to an accumulation of dihydrocortisol, an intermediate not found in nonglaucomatous trabecular meshwork cells (TMPOAG cells). Further, dihydrocortisol was shown to potentiate both cortisol and dexamethasone-induced nuclear translocation of the cytoplasmic glucocorticoid receptor in the rabbit iris-ciliary body. These observations suggest a mechanism for the sensitivity of POAG patients to exogenous glucocorticoids and for the ocular hypertension seen in these same patients. Techniques have been developed for culturing of cells from trabecular meshwork specimens (surgical and autopsy) that will allow us to test our hypothesis of an etiologic relationship between abnormal cortisol metabolism and POAG. Additional TMPOAG and TMnonPOAG cell lines will be developed to determine the incidence of the aberrant cortisol metabolism in POAG. Studies with TM cells from patients with secondary glaucoma will serve as controls for the effects of prior glaucoma therapy and chronic ocular hypertension. The enzymatic basis for this altered cortisol metabolism in TMPOAG cell lines will be investigated. The effects of enzyme inhibitors and inducers will be studied in order to determine whether the abnormal accumulation of dihydrocortisol can be prevented. In addition, glucocorticoid antagonists may be found to block the dihydrocortisol potentiation of glucorticoid-induced nuclear translocation of its receptor and its subsequent biological effects. Those antagonists that are found to be of value in in vitro studies of the human ouflow region (angle) will be studied for their ability to block the pressure raising effects of glucocorticoids and their metabolites in young rabbits. These studies may lead to information that can become the basis for new therapies (enzyme modifiers and glucocorticoid antagonists) for the treatment of POAG.